Reperfusion in acute myocardial infarction

Studies of the pathophysiology of acute myocardial infarction (AMI) have shown that in most pa- tients a thrombus forms over a ruptured ather- oma in the infarct-related coronary artery and obstructs the artery

Molecular dynamics beyonds the limits: massive scaling on 72 racks of a BlueGene/P and supercooled glass transition of a 1 billion particles system

We report scaling results on the world's largest supercomputer of our recently developed Billions-Body Molecular Dynamics (BBMD) package, which was especially designed for massively parallel simulations of the atomic dynamics in structural glasses and amorphous materials. The code was able to scale up to 72 racks of an IBM BlueGene/P, with a measured 89% efficiency for a system with 100 billion particles. The code speed, with less than 0.14 seconds per iteration in the case of 1 billion particles, paves the way to the study of billion-body structural glasses with a resolution increase of two orders of magnitude with respect to the largest simulation ever reported. We demonstrate the effectiveness of our code by studying the liquid-glass transition of an exceptionally large system made by a binary mixture of 1 billion particles.Comment: 14 pages, 8 figures, submitted to Journal of Computational Physic

1999 Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction)

The American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for the Management of Patients With Acute Myocardial Infarction have been reviewed over the past 21/2years since their initial publication (J Am Coll Cardiol 1996;28:1328–428) to ensure their continued relevancy. The guidelines have been updated to include the most significant advances that have occurred in the management of patients with acute myocardial infarction (AMI) during that time frame. This Update was developed to keep the guidelines current without republishing them in their entirety. The Update represents a new procedure of the ACC/AHA Task Force on Practice Guidelines. These guidelines will be reviewed and updated as necessary until it is deemed appropriate to revise and republish the entire document

1999 Update: ACC/AHA Guidelines for the Management of Patients with Acute Myocardial Infarction: Executive Summary and Recommendations: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction)

The American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for the Management of Patients With Acute Myocardial Infarction have been reviewed over the past 2.5 years since their initial publication in the Journal of the American College of Cardiology (1996;28:1328–1428) to ensure their continued relevancy. The guidelines have been updated to include the most significant advances that have occurred in the management of patients with acute myocardial infarction (AMI) during that time frame. This update was developed to keep the guidelines current without republishing the entire document. This effort represents a new procedure of the ACC/AHA Task Force on Practice Guidelines. These guidelines will be reviewed and updated as necessary until it is deemed appropriate to revise and republish the entire document

1999 Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction)

The American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for the Management of Patients With Acute Myocardial Infarction have been reviewed over the past 21/2years since their initial publication (J Am Coll Cardiol 1996;28:1328–428) to ensure their continued relevancy. The guidelines have been updated to include the most significant advances that have occurred in the management of patients with acute myocardial infarction (AMI) during that time frame. This Update was developed to keep the guidelines current without republishing them in their entirety. The Update represents a new procedure of the ACC/AHA Task Force on Practice Guidelines. These guidelines will be reviewed and updated as necessary until it is deemed appropriate to revise and republish the entire document

A Rare Functional Noncoding Variant at the GWAS-Implicated MIR137/MIR2682 Locus Might Confer Risk to Schizophrenia and Bipolar Disorder

Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) <0.5%. The rare variant burden in promoters and enhancers, but not insulators, was associated with SZ (p = 0.021 for MAF < 0.5%, p = 0.003 for MAF < 0.1%). A rare enhancer SNP, 1:g.98515539A>T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10−4). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression

Characterisation of age and polarity at onset in bipolar disorder

Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses

Upregulating the positive affect system in anxiety and depression: Outcomes of a positive activity intervention

BackgroundResearch suggests that the positive affect system may be an important yet underexplored treatment target in anxiety and depression. Existing interventions primarily target the negative affect system, yielding modest effects on measures of positive emotions and associated outcomes (e.g., psychological well-being). The objective of the present pilot study was to evaluate the efficacy of a new transdiagnostic positive activity intervention (PAI) for anxiety and depression.MethodTwenty-nine treatment-seeking individuals presenting with clinically impairing symptoms of anxiety and/or depression were randomly allocated to a 10-session protocol comprised of PAIs previously shown in nonclinical samples to improve positive thinking, emotions, and behaviors (e.g., gratitude, acts of kindness, optimism; n = 16) or a waitlist (WL) condition (n = 13). Participants were assessed at pre- and posttreatment, as well as 3- and 6-month follow-up, on measures of positive and negative affect, symptoms, and psychological well-being. ClinicalTrials.gov Identifier: NCT02330627 RESULTS: The PAI group displayed significantly larger improvements in positive affect and psychological well-being from pre- to posttreatment compared to WL. Posttreatment and follow-up scores in the PAI group were comparable to general population norms. The PAI regimen also resulted in significantly larger reductions in negative affect, as well as anxiety and depression symptoms, compared to WL. Improvements across all outcomes were large in magnitude and maintained over a 6-month follow-up period.ConclusionsTargeting the positive affect system through a multicomponent PAI regimen may be beneficial for generating improvements in positive emotions and well-being, as well as reducing negative affect and symptoms, in individuals with clinically impairing anxiety or depression

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe